Advertisement

Overdose of Etizolam: The Abuse and Rise of a Benzodiazepine Analog

      To the Editor:
      Etizolam is a theinodiazepine, structurally different but pharmacologically similar to benzodiazepines with gamma-aminobutyric acid type A receptor agonism.
      • Tsumagari T.
      • Nakajima A.
      • Fukuda T.
      • et al.
      Pharmacological properties of 6-(o-chlorophenyl)-8-ethyl-1-methyl-4H-s-triazolo[3,4-c]thieno[2,3-e][1,4]diazepine(Y-7131), a new anti-anxiety drug.
      It is approved for pharmaceutical use in some areas but is available for Internet purchase in the United States and many other countries for research purposes. It is increasing in popularity as a recreational “research chemical.” Recent unpublished data from the American Association of Poison Control Centers in the United States has shown an incremental increase in etizolam-related cases each year since 2011, with 41 cases reported as of August 2014. There is little reported in the English literature about the toxic effects of etizolam overdose.
      A 31-year-old man presented to our emergency department (ED) after being found unresponsive and bradypneic next to an empty syringe of alleged heroin. By reports, he had also ingested a large quantity of etizolam tablets throughout the day. Out-of-hospital intranasal naloxone, dose of 2 mg, resulted in partial reversal, with improvement of respiratory rate but minimal improvement of his mental status. On arrival to the ED, vital signs were as follows: pulse rate 115 beats/min, respiratory rate 12 breaths/min, blood pressure 132/64 mm Hg, temperature 98.9°F (37.2°C), and pulse oximetry 100% on nonrebreather mask at 15 L/min. He arrived obtunded, he moaned, and he localized painful stimuli. Pupils were pinpoint. Given his profound sedation despite naloxone administration, a trial of 0.2 mg of intravenous flumazenil was used to attempt reversal of etizolam and potentially avoid intubation and limit need for expanded diagnostics. It caused immediate and complete reversal. Initial remarkable laboratory diagnostics included pH 7.30 and pCO2 61 mm Hg on a venous blood gas test, creatinine level of 1.19 mg/dL, glucose level of 116 mg/dL, and WBC count of 18.6 × 1000/mm3. Ethanol, acetaminophen, and salicylates were not detected. ECG demonstrated narrow complex sinus tachycardia. Standard qualitative urine drug screen result was positive for opiates and benzodiazepines. Two hours after arrival, the patient once again became somnolent and bradypneic; he received an additional 2 mg of naloxone intravenously, with complete return to full alertness. He was discharged home neurologically intact after approximately 8 hours of observation.
      Confirmatory testing with liquid chromatography/mass spectroscopy of the urine identified the following: codeine level 322 ng/mL, morphine level greater than 1,000 ng/mL, and 6-acetyl morphine level 272 ng/mL, suggesting recent heroin use. No measurable amounts of any of the classic benzodiazepines or metabolites routinely tested at our laboratory were detected. Separate external analysis of initial serum sample quantitated an etizolam concentration of 103 ng/mL. Previous studies have demonstrated that peak and average etizolam concentrations in healthy young men after 0.5 mg twice-daily oral dosing were 9.3 and 3.4 ng/mL, respectively.
      • Fracasso C.
      • Confalonieri S.
      • Garattini S.
      • et al.
      Single and multiple dose pharmacokinetics of etizolam in healthy subjects.
      Nakamae et al
      • Nakamae T.
      • Shinozuka T.
      • Sasaki C.
      • et al.
      Case report: etizolam and its major metabolites in two unnatural death cases.
      reported postmortem analysis of the “unnatural death” of a 59-year-old woman who had a serum etizolam concentration of 263.7 ng/mL.
      In summary, etizolam has sedative and hypnotic effects typical of a benzodiazepine, appears to be reversible with flumazenil, and is a widely available research chemical for purchase through the Internet. The risks of reversal should always be considered, especially in patients with benzodiazepine dependence. Clinicians should be aware of its potential adverse effects, as well as its increasing presence.

      References

        • Tsumagari T.
        • Nakajima A.
        • Fukuda T.
        • et al.
        Pharmacological properties of 6-(o-chlorophenyl)-8-ethyl-1-methyl-4H-s-triazolo[3,4-c]thieno[2,3-e][1,4]diazepine(Y-7131), a new anti-anxiety drug.
        Arzneimittelforschung. 1978; 28: 1158-1164
        • Fracasso C.
        • Confalonieri S.
        • Garattini S.
        • et al.
        Single and multiple dose pharmacokinetics of etizolam in healthy subjects.
        Eur J Clin Pharmacol. 1991; 40: 181-185
        • Nakamae T.
        • Shinozuka T.
        • Sasaki C.
        • et al.
        Case report: etizolam and its major metabolites in two unnatural death cases.
        Forensic Sci Int. 2008; 182: 1-6